Alterations in glutamate neurotransmission are recognized as an important target of pharmacotherapy for alcohol dependence. Our preliminary investigations with ketamine, a glutamate modulator with potent prefrontal effects, suggest that it uniquely addresses neuroadaptations related to problematic drug and alcohol use. Alongside being safely administered to active drug users, we found that sub-anesthetic ketamine significantly increased motivation to stop cocaine use and decreased cue-induced craving when compared to an active control, 24 hours post-infusion. An ongoing clinical trial also indicates that ketamine can be feasibly administered in the setting of outpatient addiction treatment. Expanding on these findings, this project aims to examine whether ketamine will benefit problematic alcohol use in clinical settings. We will evaluate the effect of a single sub-anestheti dose of ketamine (0.11 mg/kg over 2 minutes, followed by 0.60 mg/kg over 50 minutes) on alcohol dependence in 40 non-depressed alcohol-dependent individuals engaged in Motivational Enhancement Therapy (MET). We predict that, compared to the active control midazolam, ketamine will significantly reduce percentage heavy drinking days. Secondary aims pertain to the effect of ketamine on alcohol-related deficits that implicate prefrontal dysfunction or glutamate abnormalities, such as stress sensitivity, craving, withdrawal, impulsivity, low self-efficacy, and low mindfulness. Thus, we aim to evaluate a highly innovative intervention in a manner that has the capacity to make important contributions to the field. An effect of ketamine on these outcomes would suggest that brief potent glutamatergic modulation represents a possible treatment strategy for alcohol dependence that merits further investigation.